Method for preparing risperidone

ABSTRACT

Risperidone is prepared in a high yield by reacting 2,4-difluorophenyl(4-piperidinyl)methanone oxime hydrochloride and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in an aqueous alkali hydroxide solution having an alkali hydroxide concentration in the range of 20 to 40%.

FIELD OF THE INVENTION

The present invention relates to an improved method for preparingrisperidone.

BACKGROUND OF THE INVENTION

Risperidone, which is the generic name for the compound of formula (I),3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,is a potent antipsychotic agent, especially useful for treatingschizophrenia:

There have been reported a number of methods for risperidone synthesisbut these methods generally suffer from the problems of low yield andcomplicated procedures.

For example, the benzisoxazol derivative of formula (E) obtained by ringclosure of the oxime derivative of formula (II) is coupled with thepyrimidine derivative of formula (IV) to give risperidone, as shown inScheme 1.

In Scheme 1, the coupling reaction of the benzisoxazol derivative (III)and the pyrimidine derivative (IV) may be performed by the methoddisclosed in U.S. Pat. No. 4,804,663, wherein the coupling reaction isperformed in N,N-dimethylformamide in the presence of a sodium iodidecatalyst (way a). However, this method gives a low yield of about 46%(overall yield of about 35%) due to the occurrence of side reactionssuch as self-polymerization of the benzisoxazol derivative (III).

Alternatively, the coupling reaction may be carried out using themethod, International Publication No. WO 01/85731 which uses water assolvent instead of N,N-dimethylformamide so as to suppress the sidereactions (way b). However, this method also gives an overall yield ofonly 55%.

Korean Patent Publication No. 96-9435, on the other hand, discloses amethod as illustrated in Scheme 2, wherein the compound of formula (V)obtained by coupling of the oxime derivative of formula (II) with thepyrimidine derivative of formula (IV) is subjected to ring closure inthe presence of a strong base such as sodium hydride.

However, this method still has a problem in that the overall yield isonly 45%. In addition, this method has to deal with the risk of sodiumhydride explosion.

Further, Spanish Patent No. 2,050,069 discloses a method for preparingrisperidone which is described in Scheme 3: the compound of formula(VII) obtained by coupling of the benzoylpiperidine derivative offormula (VI) and the pyrimidine derivative of formula (IV) is subjectedto oximation to give the compound (V), and ring closure thereof givesrisperidone.

This method also gives a low coupling yield of 63%, and complicatedwork-up procedures are required.

Spanish Patent No. 2,074,966 describes a method of preparing risperidoneas presented in Scheme 4, wherein the risperidone of formula (I) isobtained by the reaction of the oxazol derivative of formula (IX) andthe aminopyridin derivative of formula (VIII).

However, this method is hampered by the problem that the processes ofpreparing the starting materials of formula (VIII) and (IX) arecomplicated.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide asimple, improved method of preparing risperidone in a high yield.

In accordance with one aspect of the present invention, there isprovided a method of preparing risperidone of formula (I) whichcomprises reacting the oxime derivative of formula (II) and ahaloethylpyrimidine derivative of formula (X) in an aqueous alkalisolution:

wherein, X is a halogen.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and features of the present invention willbecome apparent from the following description of the invention, whentaken in conjunction with the accompanying drawing, in which:

FIG. 1 shows the change in the yield of risperidone (%) with theconcentration of potassium hydroxide (%), as observed in ReferenceExample.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is characterized by accomplishing the couplingreaction and the ring closure reaction in one step by way of usingselected reactants in an aqueous alkali solution having an alkalihydroxide concentration in the range of 20 to 40%.

According to the present invention, the oxime derivative of formula(II), 2,4-difluorophenyl (4-piperidinyl) methanone oxime hydrochloride,and the haloethylpyrimidine derivative of formula (X),3-(2-haloethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,are used as starting materials, which are commercially available or maybe prepared in accordance with the methods described in U.S. Pat. Nos.4,485,107 and 4,804,663.

In a preferred embodiment, the haloethylpyrimidine derivative of formula(X) may be employed in an amount ranging from 1.0 to 2.0 equivalents,preferably 1.1 to 1.3 equivalents, based on the amount of the oximederivative of formula (II).

In a preferred embodiment, the concentration of alkali hydroxide in theaqueous alkali solution used in the present invention is in the range of20 to 40% (w/v), preferably 30% (w/v), If the concentration of thealkali hydroxide is less than 20% (w/v), the yield decreases due to thegeneration of excessive by-products. On the other hand, if theconcentration of the alkali hydroxide is more than 40% (w/v), the yieldis decreased due to the increase of decomposed products.

Representative examples of the alkali hydroxide include sodiumhydroxide, potassium hydroxide, lithium hydroxide and a mixture thereof,more preferably potassium hydroxide.

In a preferred embodiment, the aqueous alkali solution may be employedin an amount ranging from 5 to 15 ml, preferably 7 to 11 ml based on 1 gof the oxime derivative of formula (II).

In a preferred embodiment, the inventive reaction may be conducted at atemperature in the range of 100 to 140° C., preferably 100 to 130° C.for 1 to 6 hours, preferably, 1.5 to 3 hours.

In accordance with the present invention, risperidone can be obtained ina much higher yield of at least 80% than previously possible. Further,according to the present invention, the conventional coupling and thering closure reactions, which comprise several cumbersome steps can beperformed simultaneously in one step. In addition, risperidone obtainedin the present invention may be refined to a purity of 99.5% or more, bya simple recrystallization procedure.

The following Examples are intended to further illustrate the presentinvention without limiting its scope.

Further, percentages given below for solid in solid mixture, liquid inliquid, and solid in liquid are on a wt/wt, vol/vol and wt/vol basis,respectively, and all the reactions were carried out at roomtemperature, unless specifically indicated otherwise.

PREPARATION EXAMPLE 1 Preparation of2,4-difluorophenyl(4-piperidinyl)methanone oxime hydrochloride (thecompound of formula II)

A) Preparation of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine

67 g of 1,3-difluorobenzene and 133 g of ammonium chloride were added to150 ml of dichloromethane, and then the mixture was cooled to roomtemperature. 98 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml ofdichloromethane was added thereto dropwise, and then the mixture wasstirred at an elevated temperature for 3 hours. The reaction mixture waspoured to a mixture of ice and hydrochloric acid, and the resultingmixture was extracted with 200 ml of dichloromethane. The organic phasewas separated, dried over anhydrous magnesium sulfate, filtered, and thesolvent was removed from the filtrate to obtain 55.9 g of the titlecompound (yield: 41%).

B) Preparation of 2,4-difluorophenyl(4-piperidinyl)methanonehydrochloride

56 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine obtained in step A)was added to 190 ml of 6N hydrochloric acid, and then, the resultingmixture was refluxed for 5 hours. The reaction mixture was concentratedunder a reduced pressure, 200 ml of 2-propanol was added to the residue,and then the mixture was stirred. The resulting solid was filtered anddried to obtain 46.6 g of the title compound (yield: 85%).

C) Preparation of 2,4-difluorophenyl(4-piperidinyl)methanone oximehydrochloride

30 g of 2,4-difluorophenyl(4-piperidinyl)methanone hydrochlorideobtained in step B) and 30 g of hydroxylamine hydrochloride were addedto 50 ml of ethanol. 29.5 ml of N,N-dimethylethanolamine was addedthereto dropwise while stirring at room temperature, and then themixture was refluxed for 3 hours. The reaction mixture was cooled toroom temperature, and the precipitated solid was filtered and dried toobtain 26.4 g of the title compound as a white crystal (yield: 96%).

PREPARATION EXAMPLE 2 Preparation of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound of formula X)

A) Preparation of3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

40 g of 2-aminopyridine and 75 ml of 3-acetyl-4,5-dihydro-2(3H)-furanonewere added to 1.0 L of toluene, and then 200 ml of phosphorusoxychloride was added thereto dropwise over 1 hour. The resultingmixture was slowly heated and refluxed for 5 hours. The reaction mixturewas concentrated under a reduced pressure and the residue was poured toa mixture of ice and ammonia water. The resulting solid was extractedwith 1.0L of dichloromethane, dried and filtered. The filtrate wasconcentrated under a reduced pressure to remove dichloromethane and 500ml of isopropanol was added to the residue. The resulting crystal wasfiltered, washed and dried to obtain 48.1 g of the title compound as aoff-white crystal (yield: 52%).

B) Preparation of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

28 g of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneobtained in step A) was dissolved in 90 ml of 6N hydrochloric acid, 2.8g of 10%-palladium was added thereto, and then the mixture washydrogenated under a hydrogen pressure of 35 psi at room temperature for8 hours. The reaction mixture was filtered through Cellite and thefiltrate was concentrated under a reduced pressure, 200 ml ofisopropanol was added to the residue, and then the mixture was stirred.The solid was filtered and dried to obtain 25.1 g of the title compoundas a white crystal (yield: 90%).

EXAMPLE 1 Preparation of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(risperidone)

2.77 g of 2,4-difluorophenyl(4-piperidinyl)methanone oxime hydrochlorideobtained in Preparation Example 1 and 2.26 g of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneobtained in Preparation Example 2 were added to 27 ml of 30% aqueouspotassium hydroxide, and then the resulting mixture was stirred at 120to 130° C. for 90 minutes. The reaction mixture was cooled to roomtemperature, filtered, and the obtained solid was added to 16 ml ofN,N-dimethylformamide. The resulting suspension was heated to 80° C.,left at that temperature for 5 minutes, and then slowly cooled to roomtemperature. The resulting crystal was filtered, washed with 5 ml ofwater and dried to obtain 3.39 g of the title compound as a whitecrystal (yield: 82%).

Melting point: 167˜169° C.;

Purity: 99.7% (by HPLC);

¹H-NMR (300 MHz, CDCl₃): δ 7.65–7.61 (m, 1H), 7.18–7.14 (m, 1H),7.00–6.94 (m, 1H), 3.87–3.83 (m, 2H), 3.12–3.07 (m, 2H), 2.97–3.02 (m,1H), 2.81–2.76 (m, 2H), 2.71–2.66 (m, 2H), 2.48–2.43 (m, 2H), 2.23 (s,3H), 2.34–2.19 (m, 2H), 2.05–2.01 (m, 4H), 1.87–1.79 (m, 4H).

EXAMPLE 2 Preparation of3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(risperidone)

The procedure of Example 1 was repeated except that 40% aqueouspotassium hydroxide was used to obtain 3.27 g of the title compound as awhite crystal (yield: 80%).

Purity: 99.5% (by HPLC);

Melting point and ¹H-NMR data were the same as in Example 1.

COMPARATIVE EXAMPLE Preparation of Risperidone in Accordance withInternational Publication No. WO 01/85731

A) Preparation of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine (thecompound of formula III)

5.52 g of 2,4-difluorophenyl(4-piperidinyl)methanone oxime hydrochlorideobtained in Preparation Example 1 was added to 25 ml of 50% potassiumhydroxide, and then the mixture was refluxed for 4 hours. Subsequently,the reaction mixture was cooled to room temperature, extracted twicewith 25 ml portions of toluene. The combined organic phase was driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated under a reduced pressure. The resulting solid wasrecrystallized from 20 ml of ether, to obtain 3.29 g of the titlecompound (yield: 75%).

¹H-NMR (300 MHz, CDCl₃): δ 7.67–7.71 (m, 1H), 7.22–7.26 (m, 1H),6.97–7.09 (m, 1H), 3.16–3.27 (m, 3H), 1.92–2.08 (m, 4H).

B) Preparation of Risperidone

2.27 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine obtained in stepA) and 2.26 g of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneobtained in Preparation Example 2 were added to a solution of 2.25 g ofNa₂CO₃ in 12 ml of water. The resulting mixture was stirred at 85 to 90°C. for 4 hours, cooled to room temperature, and filtered. The resultingsolid was added to 16 ml of N,N-dimethylformamide. The resultingsuspension was heated to 80° C., left at that temperature for 5 minutes,and then slowly cooled to room temperature. The crystal was filtered,washed with 5 ml of water and dried to obtain 3.02 g of the titlecompound as a white crystal (yield: 73%).

The Melting Point and ¹H-NMR Data Were the Same as in Example 1.

REFERENCE EXAMPLE Change of the Yield of Risperidone (%) Depending onthe Concentration of Potassium Hydroxide (%)

The procedure of Example 1 was repeated using 10, 15, 20, 30, 40, 50 or60% aqueous potassium hydroxide and the yield of risperidone (by HPLC)was examined. The results are shown in Table 1 and FIG. 1.

TABLE 1 Concentration of 10 15 20 30 40 50 60 potassium hydroxide (%)Yield of risperidone (%) 40 67 86 91 85 72 60

As shown in Table 1 and FIG. 1, the yield of risperidone varies with theconcentration of potassium hydroxide. The use of a potassium hydroxideconcentration in the range of 20 to 40% provides risperidone at a goodyield of at least 80%.

For reference, the comparison of the yields of risperidone according tothe present invention and prior arts methods are shown in Table 2, forthe purpose of verification of the effects of the present invention.

TABLE 2 Yield (%) Coupling Ring closure Overall reaction reactionreaction U.S. Pat. No. 4,804,663 46 76 35 International Publication No.72 76 55 WO 01/85731 Korean Patent No. 96-9435 77 58 45 Spanish PatentNo. 2,050,069 63 85 54 Present invention performed simultaneously noless by one step than 80

As shown in Table 2, the method of the present invention is capable ofproviding risperidone in a markedly higher yield than any of theconventional methods.

While the invention has been described with respect to the abovespecific embodiments, it should be recognized that various modificationsand changes may be made to the invention by those skilled in the artwhich also fall within the scope of the invention as defined by theappended claims.

1. A method of preparing risperidone of formula (I) which comprisesreacting an oxime derivative of formula (II) with a haloethylpyrimidinederivative of formula (X) in a 20 to 40% (w/v) aqueous alkali hydroxidesolution:

wherein, X is a halogen.
 2. The method of claim 1, wherein the alkalihydroxide is selected from the group consisting of sodium hydroxide,potassium hydroxide, lithium hydroxide and a mixture thereof.
 3. Themethod of claim 2, wherein the alkali hydroxide is potassium hydroxide.4. The method of claim 1, wherein the aqueous alkali solution isemployed in an amount ranging from 5 to 15 ml based on 1 g of the oximederivative of formula (II).
 5. The method of claim 1, wherein thehaloethylpyrimidine derivative of formula (X) is employed in an amountranging from 1.0 to 2.0 equivalents based on the amount of the oximederivative of formula (II).
 6. The method of claim 1, wherein thereaction is conducted at a temperature in the range of 100 to 140° C.